This application is aimed at developing, optimizing and validating positron labeled ligands for the beta1 and beta2-sub-types of the beta- adrenergic receptor. The optimum ligands will have suitable binding characteristics to measure the receptor concentration and association constant in vivo. A series of ligands, labeled with the short lived positron emitting radionuclide fluorine-18, will be synthesized and their kinetic receptor binding properties examined in cells transfected with the pure beta1 and beta2 receptor protein, the isolated rat heart, in dogs using positron imaging techniques and finally in normal human volunteers. Developing a labeled ligand to study the beta-adrenergic system in vivo has proved difficult. Ligands which work well in vitro do not show receptor mediated binding in vivo. Others, with smaller equilibrium dissociation constants have shown receptor mediated binding that is largely independent of receptor concentration. The data obtained from our ligands will be modeled using distributed physiological models and examined for sensitivity to the receptor concentration. This data will be correlated to the partition coefficient (lipophillicity) of the ligand (how it is delivered from the blood to the tissues) and the association and dissociation rates, (kon and koff). These data will then be used to prepare modified ligands in which the lipophillicity and the association rates will be modified to more closely fit the ideal until a satisfactory agent has been obtained. The synthesis of a range of ligands will be straightforward as general methods for preparing most of the labeled beta-adrenergic ligands have already been developed. Beta-Adrenergic receptors play an essential role in the regulation and control of the heart with the beta1 receptors being responsible for the local control of the heart whereas both the beta1 and beta2 receptors are part of the systemic control. Abnormalities in the beta-adrenergic systems are thought to be involved in a number of heart disease when both numbers and function of the receptors change. These include sudden death, arrhythmia s and congestive and ischemic myopathies and chronic heart failure. Modern therapy s are become more sophisticated with agonists and antagonists that are more selective for various sub-types of the adrenergic receptor system. However our knowledge of the role these receptors play in diseases states is limited by our ability to measure them in vivo. The successful outcome of this work will be a method that permits the measurement of the beta-adrenergic receptor in vivo in humans in a sequential fashion that can be used to select and monitor therapies in patients with diseases involving the beta-adrenergic receptor system.